BCL11A interacts with SOX2 to control the expression of epigenetic regulators in lung squamous carcinoma

Nat Commun. 2018 Aug 20;9(1):3327. doi: 10.1038/s41467-018-05790-5.

Abstract

Patients diagnosed with lung squamous cell carcinoma (LUSC) have limited targeted therapies. We report here the identification and characterisation of BCL11A, as a LUSC oncogene. Analysis of cancer genomics datasets revealed BCL11A to be upregulated in LUSC but not in lung adenocarcinoma (LUAD). Experimentally we demonstrate that non-physiological levels of BCL11A in vitro and in vivo promote squamous-like phenotypes, while its knockdown abolishes xenograft tumour formation. At the molecular level we found that BCL11A is transcriptionally regulated by SOX2 and is required for its oncogenic functions. Furthermore, we show that BCL11A and SOX2 regulate the expression of several transcription factors, including SETD8. We demonstrate that shRNA-mediated or pharmacological inhibition of SETD8 selectively inhibits LUSC growth. Collectively, our study indicates that BCL11A is integral to LUSC pathology and highlights the disruption of the BCL11A-SOX2 transcriptional programme as a novel candidate for drug development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / genetics*
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Epigenesis, Genetic*
  • Gene Expression Regulation, Neoplastic*
  • Gene Knockdown Techniques
  • Genetic Loci
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Lung / pathology
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Mice
  • Nuclear Proteins / metabolism*
  • Oncogenes
  • Organoids / pathology
  • Protein Binding
  • Repressor Proteins
  • SOXB1 Transcription Factors / metabolism*

Substances

  • BCL11A protein, human
  • Carrier Proteins
  • Nuclear Proteins
  • Repressor Proteins
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • Histone-Lysine N-Methyltransferase
  • KMT5A protein, human